P1014: OVERALL SURVIVAL IN PATIENTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS RECEIVING AVAPRITINIB VERSUS MIDOSTAURIN OR CLADRIBINE
Authors: A. Reiter, J. Gotlib, I. Álvarez-Twose, D. H. Radia, J. Luebke, P. J. Bobbili, A. Wang, C. Norregaard, S. Dimitrijević, E. Sullivan, M. Louie-Gao, J. Schwaab, I. A. Galinsky, C. Perkins, W. R. Sperr, P. Sriskandarajah, A. Chin, S. R. Sendhil, M. S. Duh, P. Valent, D. J. DeAngelo
Journal: HemaSphere (2022)

Background: Avapritinib, a selective KIT D816V inhibitor, was approved for the treatment of adults with advanced systemic mastocytosis (AdvSM) in the United States (US), based on two single-arm trials: Phase 1 EXPLORER (NCT02561988) and Phase 2 PATHFINDER (NCT03580655). No randomized controlled trial (RCT) has been conducted comparing efficacy of avapritinib versus alternative therapies for AdvSM. Aims: This study (NCT04695431) compared overall survival (OS) between AdvSM patients treated with avapritinib in the EXPLORER and PATHFINDER trials and those treated with midostaurin or cladribine in real-world clinical practice. Methods: Pooled data from the EXPLORER and PATHFINDER trials were compared with data for patients with AdvSM obtained through a multi-center, global, observational, retrospective chart review study conducted at 6 study sites (4 European, 2 US). Patients treated with midostaurin or cladribine were identified using inclusion/exclusion criteria similar to the trials and could contribute multiple lines of therapy (LOTs) to the analysis. OS, assessed using Kaplan-Meier analysis, was defined as time from initiation of avapritinib, midostaurin, or cladribine to death from any cause; patients were censored at date of last follow-up if alive. Inverse probability of treatment weighting (IPTW) was used to adjust for differences in key variables between treatment cohorts, including age, sex, AdvSM subtype, anemia, thrombocytopenia, leukocyte count, skin involvement, number and type of prior treatments, performance status, serum tryptase level, and presence of SRSF2/ASXL1/RUNX1 mutations. IPTW-weighted Cox proportional hazards models, adjusted for variables that remained unbalanced after weighting, were used to compare OS between cohorts. Results: This analysis included 176 patients treated with avapritinib, 94 treated with midostaurin (LOT, n=99), and 44 treated with cladribine (LOT, n=49). Median (range) age was 68 (31−88) for avapritinib, 69 (26−87) for midostaurin, and 66 (45−88) years for cladribine patients. 103 (59%) avapritinib patients were male, versus 64 (68%) in the midostaurin and 27 (61%) in the cladribine cohort. In the avapritinib cohort, 136 (77%) patients from both trials were dosed at ≤200mg and 40 (23%) patients, all from EXPLORER, were dosed at ≥300mg. In unweighted analysis of avapritinib versus midostaurin, mean follow-up durations were 17.9 and 27.9 months, respectively, during which 34 (19%) avapritinib patients and 56 (60%) midostaurin patients died. Median OS was not reached (NR) (95% CI: 46.9, not estimable) in the avapritinib cohort and was 28.6 months (95% CI: 18.2, 44.6) in the midostaurin cohort (Figure 1). In weighted Cox analysis, OS was significantly improved in the avapritinib versus midostaurin cohort (hazard ratio [HR] [95% CI]: 0.59 [0.36, 0.97]; P<0.001). The mean-follow-up duration for the cladribine cohort was 24.2 months, during which 29 (66%) patients died. The median OS in the cladribine cohort was 23.4 months (95% CI: 14.8, 40.6). Weighted Cox analysis showed that OS was significantly improved in the avapritinib versus cladribine cohort (HR [95% CI]: 0.32 [0.15, 0.67]; P=0.003). Image:Summary/Conclusion: The results from this study indicate that AdvSM patients treated with avapritinib in clinical trials experienced significantly improved survival compared with patients treated with midostaurin or cladribine in the real world. Given the lack of RCTs, these data offer essential insights into the improved survival of patients treated with avapritinib compared to alternative therapies for AdvSM.